ES2414434T3 - Solid amorphous dispersions of 7-chloro-N, N, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino [4,5-b] indole-1-acetamide - Google Patents

Abstract

A solid dispersion comprising 7-chloro-N, N, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino [4,5-b] indole-1-acetamide substantially amorphous and a stabilizing polymer selected from the group consisting of dehydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate, and a polymethacrylate, in which substantially amorphous means that at least 80% of the drug substance in the dispersion is in an amorphous form.

Description

Solid amorphous dispersions of 7-chloro-N, N, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino [4,5-b] indole-1-acetamide

The present invention relates to amorphous solid dispersions of 7-chloro-N, N, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro4H-pyridazino [4,5-b] indole-1-acetamide, a pharmacological agent that has a high affinity for peripheral type benzodiazepine receptors.

This invention also relates to processes for the preparation of these solid amorphous dispersions, to pharmaceutical compositions that include these dispersions, and to methods for their use for the prevention and treatment of diseases related to peripheral-type benzodiazepine receptors.

Background of the invention

7-Chloro-N, N, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino [4,5-b] indole-1-acetamide, which has the structure of formula ( I):

It has a high affinity for peripheral type benzodiazepine receptors. The preparation, physical properties and beneficial pharmacological properties of 7-chloro-N, N, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino [4,5b] indole-1-acetamide they are described, for example, in US Patent No. 6,262,045 and, in particular, US Patent No. 6,395,729.

WO 2005/034999 A2 describes oral dosage forms comprising 7-chloro-N, N, 5-trimethyl-4oxo-3-phenyl-3,5-dihydro-4H-pyridazino [4,5-b] indole- 1-acetamide and a poloxamer.

The limited solubility of 7-chloro-N, N, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino [4,5-b] indole-1-crystalline acetamide, prepared according to Example 1 of US Patent No. 6,395,729, in aqueous solutions and solvents of non-aqueous formulations presents difficulties for the administration and preservation of formulations containing this compound. Preliminary studies with conventional formulations using this crystalline solid (such as formulations prepared by wet granulation or dry mixing processes using conventional excipients well known to those skilled in the art) have led to limited absorption of the drug.

Attempts to improve the solubility of the pure drug substance, such as by preparing and using amorphous forms of 7-chloro-N, N, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H -piridazino [4,5-b] indole-1 acetamide, have produced a drug substance with limited physical stability. For example, this drug substance crystallized over time.

It has now been discovered that certain polymers are useful for preparing dispersions of 7-chloro-N, N, 5-trimethyl-4-oxo3-phenyl-3,5-dihydro-4H-pyridazino [4,5-b] indole-1 Solid amorphous acetamide that have significant improvements in solubility compared to conventional formulations, and also have significant improvements in physical stability against the amorphous drug substance alone. It is known that solid amorphous dispersions in polymers of poorly soluble drugs generally improve the solubility of drug products. However, these dispersions, in general, are unstable over time. Amorphous dispersions of drugs in polymers tend to become crystalline forms over time, which can lead to inappropriate dosing due to differences in the bioavailability and solubility of the crystalline drug material compared to the amorphous drug material. One skilled in the art cannot predict which polymers, if any, will be useful for preparing stable amorphous dispersions for a particular drug product. The present invention, however, provides these stable amorphous dispersions with better solubility.

Summary of the invention

The present invention provides solid dispersions comprising 7-chloro-N, N, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino [4,5-b] indole-1-acetamide substantially amorphous and a stabilizing polymer selected from the group consisting of hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, succinate acetate

hydroxypropylmethylcellulose, and a polymethacrylate, in which substantially amorphous means that at least 80% of the drug substance in the dispersion is in an amorphous form.

The present invention also provides processes for preparing and compositions comprising the solid amorphous dispersions of the present invention, and methods for their use.

Brief description of the drawings

Figure 1 is an X-ray powder diffractogram of a solid amorphous dispersion of 7-chloro-N, N, 5-trimethyl-4-oxo3-phenyl-3,5-dihydro-4H-pyridazino [4,5-b ] indole-1-acetamide in hydroxypropylmethylcellulose phthalate under stressful and non-stressful conditions.

Figure 2 is an X-ray powder diffractogram of a solid amorphous dispersion of 7-chloro-N, N, 5-trimethyl-4-oxo3-phenyl-3,5-dihydro-4H-pyridazino [4,5-b ] indole-1-acetamide in hydroxypropylmethylcellulose acetate succinate under stressful and non-stressful conditions.

Figure 3 is an X-ray powder diffractogram of a solid amorphous dispersion of 7-chloro-N, N, 5-trimethyl-4-oxo3-phenyl-3,5-dihydro-4H-pyridazino [4,5-b ] indole-1-acetamide in cellulose acetate phthalate under stressful and non-stressful conditions.

Figure 4 is an X-ray powder diffractogram of a solid amorphous dispersion of 7-chloro-N, N, 5-trimethyl-4-oxo3-phenyl-3,5-dihydro-4H-pyridazino [4,5-b ] indole-1-acetamide in polymeric polymethacrylate, EUDRAGIT® L 100, under stressful and non-stressful conditions.

Figure 5 is an X-ray powder diffractogram of a solid amorphous dispersion of 7-chloro-N, N, 5-trimethyl-4-oxo3-phenyl-3,5-dihydro-4H-pyridazino [4,5-b ] indole-1-acetamide in hydroxypropylcellulose under stressful and non-stressful conditions.

Figure 6 is an X-ray powder diffractogram of a solid amorphous dispersion of 7-chloro-N, N, 5-trimethyl-4-oxo3-phenyl-1,5-dihydro-4H-pyridazino [4,5-b ] indole-1-acetamide in polyvinylpyrrolidone under stressful and non-stressful conditions.

Figure 7 is an X-ray powder diffractogram of a solid amorphous dispersion of 7-chloro-N, N, 5-trimethyl-4-oxo3-phenyl-3,5-dihydro-4H-pyridazino [4,5-b ] indole-1-acetamide in polyvinylpyrrolidine plus 10% citric acid under stressful and non-stressful conditions.

Figure 8 is an X-ray powder diffractogram of a solid amorphous dispersion of 7-chloro-N, N, 5-trimethyl-4-oxo3-phenyl-3,5-dihydro-4H-pyridazino [4,5-b ] indole-1-acetamide in polyvinylpyrrolidone-vinyl acetate copolymer under stressful and non-stressful conditions.

Figure 9 is an X-ray powder diffractogram of a solid amorphous dispersion of 7-chloro-N, N, 5-trimethyl-4-oxo3-phenyl-3,5-dihydro-4H-pyridazino [4,5-b ] indole-1-acetamide in hydroxypropylmethylcellulose phthalate.

Figure 10 shows the results of the dissolution test showing the solubility / dissolution rate of amorphous solid dispersions of the invention, comparative amorphous solid dispersions, and the pure crystalline drug substance in aqueous 0.25% sodium lauryl sulfate / 0.01 M phosphate buffer pH 7.

Figure 11 shows the results of the dissolution test comparing the solubility / dissolution rate of an amorphous solid dispersion of 7-chloro-N, N, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro- 4H-pyridazino [4,5-b] indole-1-acetamide in hydroxypropylmethylcellulose phthalate of the present invention and pure crystalline drug substance in aqueous 0.25% sodium lauryl sulfate / 0.01 M phosphate buffer pH 7.

Detailed description of the invention

Definitions and Abbreviations

As previously used and used throughout the description of the invention, it will be understood that the following abbreviations, unless otherwise indicated, have the following meanings:

CHAP

cellulose acetate phthalate

AC

 citric acid

DCM

 dichloromethane

EtOH

ethanol

HPC

 hydroxypropyl cellulose

HPMCAS

hydroxypropylmethylcellulose acetate succinate

HPMCP

hydroxypropyl methylcellulose phthalate

PVP

 polyvinylpyrrolidone

As previously used and used throughout the description of the invention, it will be understood that the following terms, unless otherwise indicated, have the following meanings:

The term "drug substance", as used herein, refers to 7-chloro-N, N, 5-trimethyl-4-oxo-3-phenyl3,5-dihydro-4H-pyridazine [4,5- b] indole-1-acetamide.

In general, the term "solid dispersion" refers to a solid state system comprising at least two components, in which one component is dispersed through the other component or components. The term "amorphous solid dispersion", as used herein, refers to stable solid dispersions comprising the amorphous drug substance and a stabilizing polymer. An "amorphous drug substance" means that the amorphous solid dispersion containing the drug substance in a substantially solid amorphous form, which constitutes at least 80% of the drug substance in the dispersion, is in amorphous form. More preferably, at least 90%, and most preferably at least 95% of the drug substance in the dispersion is in amorphous form.

A solid that is in a "amorphous" solid state means that it is in a non-crystalline state. Amorphous solids in general have a short-range molecular arrangement of crystalline type, but not the long-range molecular compaction found in crystalline solids. The solid state form of a solid, such as the drug substance in the amorphous dispersion, can be determined by polarized light microscopy, X-ray powder diffraction (XPRD), differential scanning calorimetry (DSC), or other conventional techniques known to Those skilled in the art.

The amount of drug substance in the amorphous dispersions of the present invention ranges from about 0.1% to about 30% by weight relative to the stabilizing polymer. In a preferred embodiment, the amount of drug substance ranges from about 1% to about 25%, more preferably from about 5% to about 20% by weight relative to the stabilizing polymer.

The term "stabilizing polymer", as used herein, including the claims, refers to any hydroxypropylmethylcellulose phthalate (also known as HPMCP and / or hypromellose phthalate), cellulose acetate phthalate (also known as CAP), Hydroxypropylmethylcellulose acetate succinate (also known as HPMCAS) and polymeric polymethacrylates, such as EUDRAGIT® L 100. It is also understood that the term means mixtures of any of two or more of the polymers mentioned above. Preferred polymers of the invention include hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate, and polymeric polymethacrylate.

In the particularly preferred amorphous dispersions of the present invention, the drug substance is present in an amount of about 5% to about 20% by weight relative to the stabilizing polymer, and the stabilizing polymer is hydroxypropyl methylcellulose phthalate.

The solid amorphous dispersions are preferably prepared by dissolving the drug substance and the stabilizing polymer in a suitable solvent to form a feed solution, and then spray drying the feed solution to form the amorphous solid dispersion as a powder. A "suitable solvent", as used herein, is a solvent or solvent mixture in which the drug substance and the polymer have adequate solubility, for example, a solubility greater than about 1 mg / ml. A mixture of solvents is preferred if the drug substance and the stabilizing polymer require different solvents to obtain the desired solubility. Examples of suitable solvents include dichloromethane, chloroform, ethanol, methanol, 2-propanol, ethyl acetate, acetone, water or mixtures thereof. A preferred solvent is a mixture of dichloromethane and ethanol.

Spray drying is a process well known to those skilled in the art for preparing solid dispersions. In a preferred spray drying process of the present invention, the amorphous dispersion is formed by dispersing or dissolving the drug substance and the stabilizing polymer in a suitable solvent to form a feed solution, pumping the feed solution through an atomizer into a drying chamber, and removing the solvent to form the powder of the solid amorphous dispersion in the drying chamber. A drying chamber uses hot gases, such as forced air, nitrogen, nitrogen enriched air, or argon, to dry the particles. The feed solution can be atomized by conventional means well known in the art, such as two-fluid sonication nozzles and two-fluid non-sonication nozzles.

Although amorphous dispersions of the present invention are preferably prepared using conventional spray drying techniques, it will be understood that appropriate amorphous solid dispersions can be formed using other conventional techniques known to those skilled in the art, such as extrusion.

in the molten state, lyophilization, rotary evaporation, drum drying or other solvent removal process.

In another aspect of the invention, the pharmaceutically acceptable excipients used in the art in general are combined with the powder of the isolated amorphous solid dispersion to form a pharmaceutical composition. These pharmaceutically acceptable excipients may include one or more fillers; diluents, for example, microcrystalline cellulose, lactose, mannitol, pregelatinized starch and the like; disintegrants, for example, sodium starch glycolate, crospovidone, croscarmellose sodium and the like; lubricants, for example, magnesium stearate, sodium stearyl fumarate and the like; sweeteners, for example, sucrose, saccharin and the like; flavoring agents, for example, mint, methyl salicylate, orange flavor and the like; dyes; preservatives; buffers; and / or other excipients depending on the dosage form used.

The pharmaceutical compositions of the present invention preferably contain a therapeutically effective amount of the drug substance. The term "therapeutically effective amount", as used herein, refers to an amount of the drug substance present in the amorphous dispersion or pharmaceutical composition being administered that is sufficient to prevent the development or alleviate to some extent one or more symptoms of the disease being treated. Similarly, a therapeutically effective amount of a pharmaceutical composition refers to an amount of said composition that is sufficient to prevent the development or relieve to some extent one or more symptoms of the disease being treated. To determine the effective amount or dose, the attending physician considers a number of factors that include, but are not limited to the mammalian species; its size, age and general health; the specific disease involved; the degree of commitment

or severity of the disease; the response of the individual patient; the specific dispersion that is being administered; the route of administration; the bioavailability characteristics of the administered preparation; the selected dose regimen; the use of concomitant medication; and other relevant circumstances.

The pharmaceutical compositions of the present invention are generally administered orally to patients that include, but are not limited to mammals, for example, humans, in the form, for example, of a hard or soft gelatin capsule, a tablet. , an oblong tablet, pills, granules or a suspension.

In another embodiment, the present invention relates to dosage forms comprising the pharmaceutical compositions described herein. Dosage forms include, but are not limited to those selected from the group consisting of pills, hard or soft capsules, oblong tablets, tablets, granules and suspensions. Each dosage should contain the amount of drug substance calculated to produce the desired therapeutic effect. Typically, the pharmaceutical compositions will be administered in dosage units containing from about 2 mg to about 2000 mg of the drug substance by weight of the composition, with a range of about 10 mg to about 1000 mg being preferred.

Those skilled in the art will also appreciate that the pharmaceutical compositions of the present invention can be administered with other therapeutic and / or prophylactic agents and / or medicaments that are not medically incompatible with them.

All components of the present compositions must be pharmaceutically acceptable. As used herein, a "pharmaceutically acceptable" component is one that is suitable for use with humans and / or other animals without undue side effects (such as toxicity, irritation and allergic responses) that corresponds to a risk. reasonable profit / risk.

The present invention also relates to the use of the pharmaceutical compositions of the invention in medicine.

7-Chloro-N, N, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino [4,5-b] indole-1-acetamide is a selective and potent ligand of the receptor of peripheral benzodiazepine (PBR) and, as such, can be used for the prevention or treatment of peripheral neuropathies of different types, such as ischemic or trauma-related neuropathies, alcohol-related infectious, drug-related or genetic neuropathies, as well as Motoneural disorders, such as spinal amyotrophies and amyotrophic lateral sclerosis.

7-Chloro-N, N, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino [4,5-b] indole-1-acetamide can also be used for prevention or treatment of neurodegenerative diseases of the central nervous system, acute type such as strokes and cranial and spinal injuries, or chronic type such as autoimmune diseases (multiple sclerosis), Alzheimer's disease, Parkinson's disease and other diseases of which administration is expected of neurotrophic factors have a therapeutic effect.

7-Chloro-N, N, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino [4,5-b] indole-1-acetamide can also be used for prevention or treatment of acute or chronic renal failure, glomerulonephritis, diabetic nephropathy; for the treatment or prevention of heart diseases or disorders such as chronic heart failure, ischemia and heart failure, myocardial infarction, lower limb ischemia, coronary vasospasm, angina pectoris, pathological disorders associated with heart valves, inflammatory heart diseases, effects side effects due to cardiotoxic medications, or the subsequent effects of surgery

cardiac, atherosclerosis and its thromboembolic complications, restenosis, graft rejection, disorders linked to proliferation or incorrect migration of smooth myocytes.

7-Chloro-N, N, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino [4,5-b] indole-1-acetamide has demonstrated pharmacological activity in animal models of rheumatoid arthritis by modulating the immune response and, therefore, is also useful for the prevention or treatment of rheumatoid arthritis.

Data from the literature indicate that the peripheral-type benzodiazepine receptor may play a fundamental role in the regulation of cell proliferation and cancer processes. In general, and compared to normal tissues, a higher density of peripheral-type benzodiazepine receptors is observed in various types of tumors and cancers. Thus, 7-chloro-N, N, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino [4,5-b] indole-1-acetamide can also be used for prevention or the treatment of tumors and cancers.

Peripheral type benzodiazepine receptors are also present in the skin and, under them, 7-chloro-N, N, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazine [4 , 5-b] indole-1-acetamide can be used for prophylaxis

or the treatment of skin stresses. It is understood that the term "skin stress" means the various situations that can cause damage, particularly in the epidermis, regardless of the agent that causes this stress. This agent can be inside and / or outside the body, such as a chemical or free radical agent, or elsewhere outside, such as ultraviolet radiation.

The present invention, therefore, relates to a method for treating and / or preventing diseases related to peripheral-type benzodiazepine receptors, which comprises administering to a patient in need of such treatment or prevention a therapeutically effective amount of an amorphous dispersion of the present invention, or a therapeutically effective amount of a pharmaceutical composition of the present invention.

In one embodiment, the present invention relates to a method for treating or preventing a neurodegenerative disease, which comprises administering to a patient in need of such treatment or prevention a therapeutically effective amount of an amorphous dispersion of the present invention, or a therapeutically effective amount. of a pharmaceutical composition of the present invention.

Another embodiment of the present invention is a method for treating or preventing neuropathy, which comprises administering to a patient in need of such treatment or prevention a therapeutically effective amount of an amorphous dispersion of the present invention, or a therapeutically effective amount of a pharmaceutical composition. of the present invention.

In another embodiment, the present invention relates to a method for treating or preventing cancer or tumors, which comprises administering to a patient in need of said treatment or prevention a therapeutically effective amount of an amorphous dispersion of the present invention, or a therapeutically amount. effective of a pharmaceutical composition of the present invention.

Another embodiment of the present invention is a method for treating or preventing skin stresses, which comprises administering to a patient in need of such treatment or prevention a therapeutically effective amount of an amorphous dispersion of the present invention, or a therapeutically effective amount of a composition. Pharmaceutical of the present invention.

A preferred embodiment of the invention is a method for treating or preventing rheumatoid arthritis, which comprises administering to a patient in need of such treatment or prevention a therapeutically effective amount of an amorphous dispersion of the present invention, or a therapeutically effective amount of a composition. Pharmaceutical of the present invention.

Another preferred embodiment of the invention is a method for treating or preventing a heart disease or heart disorder, which comprises administering to a patient in need of such treatment or prevention a therapeutically effective amount of an amorphous dispersion of the present invention, or a therapeutically amount. effective of a pharmaceutical composition of the present invention.

A matter of the present invention is the use of a solid amorphous dispersion of the present invention in the manufacture of medicinal products for the treatment of diseases related to peripheral-type benzodiazepine receptors, such as neurodegenerative diseases, neuropathies, cancer or tumors, skin stress, heart disease or cardiac disorder, or rheumatoid arthritis.

The following examples will further illustrate the invention, without limiting it to them.

Example 1

Preparation of a 20% amorphous dispersion of drug substance in hydroxypropylmethylcellulose phthalate 3.2 grams of hydroxypropylmethylcellulose phthalate (HPMCP, commercially available as HP-55, Shin-Etsu Chemical. Co. Ltd., Tokyo, Japan were added ) and 0.8 g of the drug substance (which can be prepared by methods known in the art, for example, as described in US Patent No. 6,395,729) to a mixture of 72 ml of dichloromethane (DCM) and 72 ml of ethanol (EtOH). The resulting clear feed solution is

5 pumped through an ultrasonic atomizer (commercially available in Sonotek, running it at a frequency of 60 Hz in the upper spray mode with a gas inlet temperature 20 ºC and a gas outlet temperature of 18 ºC) into a drying chamber using a Harvard syringe pump with a feed rate of 2.2 ml / min. The solvent was removed to provide a solid amorphous dispersion.

10 Examples 2 to 4

The solid amorphous dispersions of Examples 2, 3 and 4 were prepared primarily according to the procedure described in Example 1, above, using the parameters listed in Table 1.

Table 1: Amorphous dispersions

Ex. Nº

Amount of drug substance Polymer type Polymer quantity Solvent system Temp. input Temp. output Feed rate

(g)     (g)     (° C) (° C) (ml / min)

2

0.8 Hydroxypropylmethylcellulose acetate succinate (HPMCAS, Shin-Etsu Chemical. Co. Ltd., Tokyo, Japan) 3.2 72 ml of DCM and 72 ml of EtOH twenty 18 2.25

3

0.8 cellulose acetate phthalate (CAP, Eastman Chemical, Kingsport, Tenn.) 3.2 72 ml of DCM and 72 ml of EtOH twenty 18 2.25

4

0.8 Polymeric polymethacrylate (commercially available as EUDRAGIT® L 100, Degussa, Germany) 3.2 72 ml of DCM and 72 ml of EtOH twenty 18 2.25

15 Comparative Examples 5 to 8

The solid amorphous dispersions of comparative examples 5, 6, 7 and 8 were prepared primarily according to the procedure described in example 1 above, using the parameters listed in Table 2. Table 2: Comparative amorphous dispersions

Eg comp. nº

Amount of drug substance (g) Polymer type Polymer quantity Solvent system Temp. input Temp. output Feed rate

(g)     (° C) (° C) (ml / min)

5

0.8 hydroxypropylcellulose (HPC, Klucel® EF, Hercules Incorporated, Wilmington, Del., USA) 3.2 72 ml of DCM and 72 ml of EtOH twenty 18 2.25

6

0.8 Polyvinylpyrrolidone (PVP, commercially available as Plasdone® K-25, International Specialty Products, Technologies, Wayne, NJ) 3.2 72 ml of DCM and 72 ml of EtOH twenty 18 2.25

7

0.8 polyvinylpyrrolidone (commercially available as Plasdone® K25) plus 10% citric acid 3.2 72 ml of DCM and 72 ml of EtOH twenty 18 2.25

8

0.8 copolymer of polyvinylpyrrolidone vinyl acetate (PVPVA, 3.2 72 ml of DCMy72 twenty 18 2.25

Eg comp. nº

Amount of drug substance (g) Polymer type Polymer quantity Solvent system Temp. input Temp. output Feed rate

(g)

(° C) (° C) (ml / min)

commercially available as Kollidon® VA 64, BASF, Germany)     ml of EtOH

Example 9

20% amorphous drug substance dispersed in HPMCP

Hydroxypropylmethylcellulose phthalate (approximately 400 g) and the drug substance (approximately 100 g) were added to a mixture of dichloromethane (approximately 3.56 L) and ethanol (approximately 3.55 L). The resulting transparent feed solution was pumped through a two-fluid nozzle atomizer with a gas inlet temperature of 44 ° C and a gas outlet temperature of 25 ° C and into a drying chamber with a feed rate of approximately 35 g / min The solvent was removed to provide approximately 500 g of the amorphous dispersion, in which the product composition was 20% drug substance / 80% HPMCP (HP-55).

Experimental data

X-ray powder diffractometry (XRPD) (Figures 1 to 9)

The XRPD patterns of Examples 1 to 4 and 9 (Figures 1 to 4 and 9, respectively) and Comparative Examples 5 to 8 (Figures 5 to 8, respectively) were obtained with a Bruker D8® X-ray powder diffractrometer ADVANCE using copper K-alpha radiation. The instrument was equipped with an optical parallel beam system, and the tube voltage and amperage were adjusted to 40 kV and 40 mA, respectively. The samples were swept at a speed of 0.1 degrees / minute or 1.0 degrees / minute at a 2-teat angle.

The initial (unstressed) XRPD patterns obtained for examples 1 to 4 and 9, and comparative examples 5 to 8 all indicate that the drug substance is substantially amorphous.

Stability studies (figures 1 to 8)

The stabilities of examples 1 to 4, and comparative examples 5 to 8 were determined after storage of the samples at 40 ° C / 15% relative humidity for three months. Other samples were also stored in a high humidity chamber at 40 ° C / 75% relative humidity for three months. A saturated aqueous solution of sodium chloride was used to generate the desired humidity for the high humidity chamber. Solid amorphous dispersions were introduced in hard gelatin capsules of size 0, then placed in high density polyethylene bottles, which were placed in the chamber at 40 ° C.

Figures 1 to 8 show the XRPD patterns for the examples initially obtained, after 3 months at 40 ° C / 15% relative humidity, and after 3 months at 40 ° C / 75% relative humidity. These patterns indicate that examples 1 to 4 (figures 1 to 4), unpredictably, remained stable (i.e., did not appreciably crystallize) even under stressful conditions, while comparative examples 5 to 8 began to crystallize under conditions stressful, as shown in the XRPD patterns in figures 5 to 8.

Dissolution study (figures 10 and 11)

The pure crystalline drug substance used in the following dissolution studies was prepared by dissolving 7-chloro-N, N, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazine [4,5-b] Indole-1-acetamide in hot N-methyl-2-pyrrolidinone (NMP), adding ethanol to form a precipitate, and isolating the solid.

The dissolution tests of examples 1 to 4, and comparative examples 5 to 8, and the pure crystalline drug substance were performed with a paddle-type drug dissolution test bath (available from Distek Inc.) at 75 rpm, and an HP 8453 UV spectrophotometer at a wavelength of 320 nm. The following parameters were used: the concentration of drug substance was 20 mg / 500 ml of medium, in which the medium was 0.25% sodium lauryl sulfate in water / 0.01 M phosphate buffer pH 7; the temperature was 37 ° C; and the sampling time interval was 10 minutes. Two containers were used for each sample.

The results of the dissolution test, shown in Figure 10, indicate that the amorphous solid dispersions of the present invention have significantly higher dissolution rates, compared to the pure crystalline drug substance and comparative examples 5 to 8.

The dissolution studies were repeated for example 9 using essentially the same procedure as described for the dissolution studies of examples 1 to 4 and comparative examples 5 to 8. The solid amorphous dispersion of example 9 shows a marked increase in dissolution rate compared to the pure crystalline drug substance. The results of this experiment are shown in Figure 11.

Bioavailability Study

The following study was conducted to determine the bioavailability of a solid dispersion formulation according to the present invention, relative to a conventional formulation under fasting conditions.

A conventional formulation and a solid dispersion of the present invention were prepared as follows:

Conventional formulation

Material

Amount (mg / capsule)

Active drug substance (micronized)

twenty

Polysorbate 80

2.00

Microcrystalline cellulose

125

Pregelatinized starch

249

Croscarmellose sodium

2.00

Magnesium stearate

2.00

10 This conventional formulation was used as a reference material and manufactured using a conventional wet granulation process and introduced into a hard gelatin capsule of size 0.

Solid dispersion

Material

Amount (mg / capsule)

Hydroxypropylmethylcellulose Phthalate

100

Active drug substance

25

The solid dispersion was prepared according to example 9, above, and introduced into a hard gelatin capsule of size 0.

15 100 mg of the active drug substance were administered in a single oral dose of the conventional formulation (n = 7) or solid dispersion (n = 8) to humans, and blood samples were collected at 0.5, 1 , 1,5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours. The samples were analyzed by LC / MS (liquid chromatography / mass spectrometry).

The results are indicated in table 3. Cmax (maximum blood concentration) and AUC (area under the

20 concentration versus time in the diagram) were significantly higher for solid dispersions, when compared to the conventional control formulation, thereby indicating the best bioavailability of the amorphous dispersions of the present invention.

Table 3: Results of the bioavailability study: serum blood levels in humans after

oral administration Example 10

Parameter

Half of)

Reference capsule (n = 7) Solid device (n = 8)

Cmax

38.5 340

(ng / ml)

(18.4) (144)

tmax

6 2.5

(h) *

(3,0, 36) (1,5, 4)

AUC0-24

500 2660

(ng.h / ml)

(217) (1270)

Tablets and capsules containing the pharmaceutical compositions of the present invention having the following composition can be produced in a conventional manner:

mg per tablet or capsule

Dispersion prepared according to example 9

300

Microcrystalline cellulose

80

Sodium starch glycolate

16

Magnesium stearate

4

Total weight of the tablet or capsule

400

Claims (26)

1. A solid dispersion comprising 7-chloro-N, N, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino [4,5-b] indole-1 acetamide substantially amorphous and a stabilizing polymer selected from the group consisting of hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate, and a polymethacrylate, in which substantially amorphous means that at least 80% of the drug substance in the dispersion is in an amorphous form . 2. The solid dispersion according to claim 1, wherein said stabilizing polymer is hydroxypropyl methylcellulose phthalate. 3. The solid dispersion according to claim 1, wherein said stabilizing polymer is cellulose acetate phthalate. 4. The solid dispersion according to claim 1, wherein said stabilizing polymer is a polymethyl acrylate. 5. The solid dispersion according to claim 1, wherein the 7-chloro-N, N, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino [4,5-b] indole -1-acetamide is present in an amount of about 0.1% to about 30% by weight relative to the weight of the stabilizing polymer. 6. The solid dispersion according to claim 5, wherein the 7-chloro-N, N, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino [4,5-b] indole -1-acetamide is present in an amount of about 1% to about 25% by weight relative to the weight of the stabilizing polymer. 7. The solid dispersion according to claim 6, wherein the 7-chloro-N, N, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino [4,5-b] indole -1-acetamide is present in an amount of about 5% to about 20% by weight relative to the weight of the stabilizing polymer. 8. The solid dispersion according to claim 7, wherein the stabilizing polymer is hydroxypropyl methylcellulose phthalate. 9. The solid dispersion according to claim 1, wherein at least 90% of the 7-chloro-N, N, 5-trimethyl-4-oxo-3-phenyl3,5-dihydro-4H-pyridazino [4, 5-b] indole-1-acetamide is in amorphous form. 10. The solid dispersion according to claim 9, wherein at least 95% of the 7-chloro-N, N, 5-trimethyl-4-oxo-3-phenyl3,5-dihydro-4H-pyridazino [4, 5-b] indole-1-acetamide is in amorphous form. 11. A pharmaceutical composition comprising a solid dispersion according to claim 1, and one or more pharmaceutically acceptable excipients. 12. A pharmaceutical composition comprising a solid dispersion according to claim 8, and one or more pharmaceutically acceptable excipients. 13. A solid dispersion according to claim 1, for use in the treatment or prevention of a neurodegenerative disease. 14. A pharmaceutical composition according to claim 11, for use in the treatment or prevention of a neurodegenerative disease. 15. A solid dispersion according to claim 1, for use in the treatment or prevention of neuropathy. 16. A pharmaceutical composition according to claim 11, for use in the treatment or prevention of neuropathy. 17. A solid dispersion according to claim 1, for use in the treatment or prevention of cancers or tumors. 18. A pharmaceutical composition according to claim 11, for use in the treatment or prevention of cancers or tumors. 19. A solid dispersion according to claim 1, for use in the treatment or prevention of skin stress. 20. A pharmaceutical composition according to claim 11, for use in the treatment or prevention of skin stress. 21. A solid dispersion according to claim 1, for use in the treatment or prevention of rheumatoid arthritis. 22. A pharmaceutical composition according to claim 11, for use in the treatment or prevention of rheumatoid arthritis. 23. A solid dispersion according to claim 1, for use in the treatment or prevention of a heart disease or a heart disorder. 24. A pharmaceutical composition according to claim 11, for use in the treatment or prevention of heart disease or heart disorder. 25. A process for preparing the solid dispersion according to claim 1 comprising the steps of: a) dissolve 7-chloro-N, N, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino [4,5-b] indole-1-acetamide and a stabilizing polymer in a suitable solvent to form a feed solution, wherein said stabilizing polymer 10 is selected from the group consisting of hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate, and a polymethacrylate b) pump the feed solution through an atomizer; Y c) remove the solvent to form the solid dispersion. 26. The process according to claim 25, wherein the suitable solvent is one or more solvents selected from the group consisting of dichloromethane, chloroform, ethanol, methanol, 2-propanol, ethyl acetate, acetone, and water. 27. The process according to claim 25, wherein the stabilizing polymer is hydroxypropylmethylcellulose phthalate, and the suitable solvent is a 50:50 by volume mixture of dichloromethane and ethanol.